Regression Of Experimental Nis-Expressing Breast Cancer Brain Metastases In Response To Radioiodide/Gemcitabine Dual Therapy

Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I-symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (I-131(-)). We show impressive enhancement of tumor response by combining I-131(-) with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression. I-131(-)/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kgx4); I-131(-) (1mCi or 2x0.5 mCi 7 days apart); and I-131(-)/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of I-131(-)-treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (similar to 20% of cells). High and low-dose I-131(-)/GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/I-131(-) delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/I-131(-) caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to I-131(-).